Management of Hormone-Responsive Postmenopausal Breast Cancer

Postmenopausal breast cancer is frequently hormone responsive and may be treated with agents that prevent estrogen activity. Tamoxifen is the most widely used of these agents, proving effective in both early and advanced disease. However, the role of tamoxifen has been challenged by the development of newer agents which have demonstrated at least equivalent activity and better tolerability, notably the nonsteroidal third-generation aromatase inhibitor anastrozole, which is currently the only other agent approved for primary adjuvant treatment of early disease and first-line treatment of advanced disease.In postmenopausal women with early breast cancer, anastrozole was associated with a significantly higher rate of disease-free survival (86.9% vs 84.5%) and a lower incidence of contralateral breast cancer than tamoxifen. Furthermore, the incidences of thromboembolic events and endometrial cancer were significantly lower with anastrozole. However, anastrozole was associated with an increase in musculoskeletal events (including fractures) and further evaluation of the clinical significance of this finding is warranted. Pharmacoeconomic analyses based on the results of this trial and conducted from different healthcare perspectives have all found anastrozole to be a cost-effective adjuvant therapy for early postmenopausal breast cancer. Clinical trial data indicate that switching patients who have already received 2 years’ tamoxifen treatment to anastrozole reduces the risk of relapse and death compared with continuing treatment with tamoxifen. Further studies are warranted to determine the optimum sequence of agents and duration of adjuvant therapy.Large well designed trials have also shown first-line anastrozole therapy is at least as effective as tamoxifen in prolonging time to disease progression and overall survival in patients with advanced disease. Current data indicate that the drug is more effective than tamoxifen in patients whose tumors are known to express the estrogen receptor. Pharmacoeconomic analyses conducted from various healthcare perspectives support the use of anastrozole as a cost-effective treatment in this indication.Anastrozole has demonstrated similar efficacy to that of other approved agents, including letrozole and fulvestrant, as second-line therapy for patients who have failed first-line therapy (in most cases with tamoxifen).In conclusion, clinical and pharmacoeconomic data support the role of anastrozole as a primary adjuvant treatment for use across the entire spectrum of breast cancer encompassing early disease through to advanced metastatic disease, and reflect current treatment guidelines. Anastrozole has also proven effective in clinical trials in the neoadjuvant setting, though its use in this setting and in breast cancer prevention remains to be fully elucidated.     

Changes in endocrine therapy: anastrozole and advanced breast cancer in postmenopausal women

Emerging data on endocrine therapies necessitates a re-evaluation of treatment strategies for advanced breast cancer. In this review, we present data from recent studies of the third-generation, nonsteroidal aromatase inhibitor (AI) anastrozole that illustrate its changing role in the treatment of postmenopausal women with advanced breast cancer. These studies demonstrate that anastrozole is now a treatment of choice as first-line therapy for patients presenting with advanced breast cancer and for patients who have progressed to advanced disease after adjuvant therapy with tamoxifen. A further trial has also shown that anastrozole is an effective and well-tolerated alternative to tamoxifen as adjuvant treatment for postmenopausal women with early breast cancer.     

Economic Evaluation of Letrozole in the Treatment of Advanced Breast Cancer in Postmenopausal Women in Canada

OBJECTIVE: To determine the cost-effectiveness of initiation of second-line hormone therapy with letrozole in the treatment of advanced breast cancer in postmenopausal women in Canada, compared to megestrol acetate. METHODS: A modified Markov model, incorporating seven health states, was designed to simulate the treatment of patients with advanced breast cancer from second-line hormone therapy to death. The model was constructed with data from a clinical trial, literature sources, and interviews with breast cancer treatment experts. Canadian experts provided information on resource utilization patterns and local costs were attached to these resources. The model was used to calculate mean survival time, time without progression, and total direct medical costs for patients initiating treatment with letrozole 2.5 mg or megestrol acetate 160 mg. RESULTS: The mean survival time and time without progression for letrozole 2.5 mg patients were 28.3 months and 19.0 months, respectively, compared to 25.7 months and 16.5 months for megestrol acetate 160 mg patients. Total treatment costs for both groups were similar with the letrozole 2.5 mg group costing dollar 20,068 per patient, dollar 1061 more than the megestrol acetate 160 mg group (dollar CAN, 1996). The cost-effectiveness ratio for letrozole 2.5 mg with respect to megestrol was dollar 5051 per year of life gained. Sensitivity analysis showed that this ratio was sensitive to variations in the probabilities governing disease progression. CONCLUSIONS: Advanced breast cancer patients initiating second-line hormone therapy with letrozole 2.5 mg have better clinical outcomes than patients receiving megestrol acetate 160 mg. Furthermore, this benefit comes at an acceptable cost to the Canadian health care system.     

Cost utility analysis of early adjuvant letrozole or anastrozole versus tamoxifen in postmenopausal women with early invasive breast cancer: the UK perspective

Five years with the aromatase inhibitors letrozole or anastrozole is clinically superior to 5 years tamoxifen in postmenopausal women with early breast cancer. This paper analyses the cost-effectiveness of the aromatase inhibitors compared to tamoxifen using the same health economic model. A Markov model describes lifetime incidence of breast cancer events and treatment-related adverse events. Probabilities of disease progression, adverse events, and utility values were estimated using secondary sources; costs of breast-cancer care were obtained from a primary costing study. The incremental cost per QALY gained of letrozole vs. tamoxifen is ￡10,379 (95% CI ￡6,705–23,574), and of anastrozole versus tamoxifen is ￡11,428 (95% CI ￡6,211–48,795). If a 5-year carry over effect for the reduction in breast cancer events is assumed, the incremental costs per QALY gained compared to tamoxifen are ￡6,253 (95% CI ￡3,675–14,766) for letrozole and ￡7,015 (95% CI ￡3,316–31,997) for anastrozole. Five years of letrozole or anastrozole therapy is cost-effective in postmenopausal women with early breast cancer. Though the respective confidence intervals show significant overlap, letrozole has a 95% probability of being more cost-effective than tamoxifen at a ￡20,000 QALY value, whilst anastrozole has an 85% probability.     

Progression-Free Survival with Fulvestrant 500 mg and Alternative Endocrine Therapies as Second-Line Treatment for Advanced Breast Cancer: A Network Meta-Analysis with Parametric Survival Models

BackgroundOuwens et al. and Jansen have presented methods for (network) meta-analysis of survival data by using a multidimensional treatment effect as an alternative to the synthesis of constant hazards ratios, which allow for a better fit to the data and the expected survival of competing interventions for cost-effectiveness analysis. However, results may be sensitive to the assumed underlying survival function.ObjectiveTo estimate the expected progression-free survival (PFS) for fulvestrant 500 mg versus alternative hormonal therapies for postmenopausal women with advanced breast cancer who relapsed previously by means of a network meta-analysis of currently available randomized controlled trials using alternative underlying survival functions.MethodsEleven randomized controlled trials were included that evaluated fulvestrant 500 mg (n = 3), fulvestrant 250 mg (n = 5), fulvestrant 250 mg loading dose (n = 3), anastrozole 1 mg (n = 3), megestrol acetate (n = 4), letrozole 2.5 mg (n = 3), letrozole 0.5 mg (n = 3), and exemestane (n = 2). PFS percentages and numbers at risk were derived from Kaplan-Meier curves and combined by means of Bayesian network meta-analysis on the basis of the difference in the shape and scale parameters of the Weibull, log-normal, and log-logistic parametric survival functions.ResultsThe log-normal distribution provided the best fit, suggesting that the proportional hazard assumption was not valid. Based on the difference in expected PFS, it was found that fulvestrant 500 mg is more efficacious than fulvestrant 250 mg, megestrol acetate, and anastrozole (−5.73 months; 95% credible interval [CrI]−10.67,−1.67). Expected PFS for fulvestrant 500 mg ranged from 10.87 (95% CrI 9.21, 13.07) to 17.02 (95% CrI 13.33, 22.02) months for the Weibull versus log-logistic distribution.ConclusionsFulvestrant 500 mg is expected to be more efficacious than fulvestrant 250 mg, megestrol acetate, and anastrozole 1 mg and at least as efficacious as exemestane and letrozole 2.5 mg in terms of PFS among postmenopausal women with advanced breast cancer after failure on endocrine therapy. The findings were not sensitive to the distribution, although the expected PFS varied substantially, emphasizing the importance of performing sensitivity analyses.     

Prospects for the primary prevention of breast cancer.

In this paper, the rationale, stage of development, and known or potential adverse effects of three potential strategies for the prevention of breast cancer are reviewed. Two methods--the use of tamoxifen in postmenopausal women and the use of luteinizing hormone (LH)-releasing hormone agonists in premenopausal women--involve hormonal manipulation. In the premenopausal period, the goal is to reduce the number of ovulatory menstrual cycles a woman experiences in order to reduce her exposure to estrogen and progesterone. Physical activity during adolescence is proposed as a nonhormonal method of accomplishing this. The use of LH-releasing hormone agonists to produce a reversible menopause can also reduce a woman's cumulative exposure to ovarian steroid hormones. Tamoxifen, which is effective in breast cancer therapy, provides endocrine control of estrogen-regulated breast tumor growth. Breast cancer chemoprevention trials using tamoxifen among postmenopausal women have been proposed, and pilot studies are under way.     

Three men with breast cancer

In three men, aged 81, 66 and 58 years, breast cancer was diagnosed. All three were treated by modified radical mastectomy and axillary-node dissection. They received tamoxifen and the first and the third patient also received radiotherapy. Presentation of these patients is usually delayed, because of the rarity of and unfamiliarity with the disease. Consequently, the disease is often in a more advanced stage at presentation and overall mortality is higher in comparison with women with breast cancer. However, survival of male patients is similar to survival of female patients when matched for age and stage. This stresses the importance of a timely diagnosis. As in women, of the known risk factors for male breast cancer, a positive family history is one of the most important ones. Modified radical mastectomy, combined with sentinel-node biopsy by experienced teams, is the standard treatment. Criteria for adjuvant systemic treatment are identical for men and women, although hormonal therapy (tamoxifen) has a more prominent place in the adjuvant setting because of the high percentage of positive hormone receptors in men.     

Optimal adjuvant hormone therapy in postmenopausal women with hormone-sensitive mammary carcinoma: tamoxifen and the aromatase inhibitors anastrozole, exemestane and letrozole

Postmenopausal patients with hormone-sensitive breast cancer may be eligible for adjuvant hormone therapy. - For years, tamoxifen was the treatment of choice. - However, the side effects associated with tamoxifen, such as endometrial cancer and thromboembolic disorders, and the search for more effective agents have led to the introduction of new hormonal therapies. - The results of randomised trials with the third-generation aromatase inhibitors anastrozole, exemestane and letrozole demonstrate improved efficacy compared to tamoxifen. - Using aromatase inhibitors, the disease-free survival is prolonged and recent data from some studies also show a benefit in overall survival. - Aromatase inhibitors are associated with specific side effects consisting of osteoporosis/increased incidence of fractures and myalgia/arthralgia.     

Survival impact of tamoxifen use for breast cancer risk reduction: projections from a patient-specific Markov model.

The authors estimate tamoxifen's impact on life expectancy among healthy women. A Markov model compared the effects of 5 years of tamoxifen on survival among 50-year-old postmenopausal women. Scenarios were explored using alternative assumptions with regard to tamoxifen's long-term effects on breast and endometrial cancer. Postmenopausal women without a uterus had substantial life expectancy gains from tamoxifen (1 to 4 months), whereas women with a uterus had such gains only if they were at a very high breast cancer risk. If tamoxifen's impact on endometrial cancer persists after treatment is discontinued, women at high risk for endometrial cancer have life expectancy losses from tamoxifen unless they are at a very high risk for breast cancer. The authors conclude that tamoxifen use among postmenopausal women is associated with substantial life expectancy gains. However, this benefit is modulated in women at increased endometrial cancer risk and depends on assumptions concerning tamoxifen's lingering effects on breast and endometrial cancer.     

Hormone receptors and breast cancer--an occasional survey

Hormone receptors are proteins, localised in the membrane, cytosol, mitochondrion or nucleus of target cells; binding of hormone to the receptor leads to alterations in intracellular activity or growth. The development of antagonists which competitively bind to receptor sites has been used clinically to block, for example, the action of androgen, histamine, adrenaline and oestrogen. In patients with breast cancer, measurements of hormone receptor activity are valuable (1) in predicting which patients with advanced disease will respond to endocrine therapy, (2) as an additional independent guide to the patients' prognosis. The anti-oestrogen, tamoxifen has few side-effects and is therefore particularly useful in the treatment of advanced disease. In addition, two trials, performed in the USA, suggest that this receptor-blocker may be valuable in the adjuvant treatment of early disease. In the UK, further trials are underway to confirm this and to assess the relationship of hormone receptor status in the primary tumour to benefit from treatment.     

Megestrol acetate for the palliation of anorexia in advanced, incurable cancer patients

Anorexia, or loss of appetite, is a troubling symptom for many patients with advanced cancer. The early observation that breast cancer patients, who were prescribed megestrol acetate as a cancer treatment, went on to increase their appetite and gain weight has given rise to a large number of clinical trials that have tested this progestational drug as a palliative agent for the cancer anorexia/weight loss syndrome. This review focuses on these trials, summarizing their findings and providing a practical approach for prescribing megestrol acetate to advanced cancer patients who suffer from the cancer anorexia/weight loss syndrome.     

Antiestrogen chemoprevention of breast cancer: critical issues and research

Estrogenic hormones play critical roles in many aspects of women's health. Therefore, the impact of any hormonal manipulation must be carefully considered. While the evidence is good that chemoprevention, or more accurately chemosuppression, of breast cancer with tamoxifen is possible, further data are needed to support the case that hormone replacement with tamoxifen in healthy postmenopausal women would provide overall health benefits. Specifically, further data are needed regarding the biological effects of tamoxifen on risk factors for cardiovascular disease, on bone, on the liver, on the uterus, and on the coagulation system. Frequency, severity, and predictors for vasomotor, gynecologic, and depressant side effects also need to be well described. These data will allow rigorous cost-effectiveness analysis of hormone replacement therapies with tamoxifen and estrogen, as well as an analysis of the cost effectiveness of a clinical trial to prove definitively critical health benefits.     

第三代芳香化酶抑制剂在绝经后乳腺癌新辅助内分泌治疗中的应用

乳腺癌新辅助内分泌治疗是指对非转移性的乳腺癌患者在应用局部治疗前进行的系统性的内分泌治疗.研究证实,第三代芳香化酶抑制剂（Aromatase inhibitors,AIs）应用于绝经后乳腺癌患者的新辅助内分泌治疗效果显著优于他莫西芬（Tamoxifen,TAM）,并且能够明显提高局部进展期乳腺癌（Locally advanced breast cancer,LABC）的手术切除率,改善巨大肿瘤和不可手术切除乳腺癌的外科治疗效果.     

Circulating testosterone and prostate-specific antigen in nipple aspirate fluid and tissue are associated with breast cancer

Preliminary evidence has associated testosterone and prostate-specific antigen (PSA) with breast cancer. Our objective was to determine whether a) testosterone levels in nipple aspirate fluid (NAF), serum, or breast tissue are associated with breast cancer; b) testosterone levels in serum are associated with levels in NAF; c) PSA in NAF, serum, or breast tissue is associated with breast cancer; and d) serum PSA is associated with NAF PSA levels. We obtained 342 NAF specimens from 171 women by means of a modified breast pump. Additionally, we collected 201 blood samples from 99 women and 51 tissue samples from 41 subjects who underwent surgical resection for suspected disease. Women currently using birth control pills or hormone replacement therapy were excluded from the study. Controlling for age and menopausal status, serum testosterone was significantly increased in women with breast cancer (p = 0.002). NAF and serum testosterone levels were not associated. Neither NAF nor tissue testosterone was associated with breast cancer. Controlling for menopausal status and age, NAF PSA was significantly decreased in women with breast cancer (p < 0.001). We did not find serum PSA to be associated with breast cancer, although we found an indication that, in postmenopausal women, its levels were lower in women with cancer. Serum PSA was associated with NAF PSA in postmenopausal women (p < 0.001). PSA levels in cancerous tissue were significantly lower than in benign breast specimens from subjects without cancer (p = 0.011), whereas levels of PSA in histologically benign specimens from subjects with cancer were intermediate. Our results suggest that serum testosterone is increased and NAF PSA is decreased in women with breast cancer, with PSA expression being higher in normal than in cancerous breast tissues. NAF and serum PSA levels in postmenopausal women are correlated, suggesting that as laboratory assessment of PSA becomes more sensitive, serum PSA may become useful in identifying women with breast cancer.     

The effect of hormone therapy on cognitive function in patients with breast cancer

Preclinical and clinical studies suggest that oestrogens have an important role in brain functioning and cognitive ability. Given that hormone therapies for breast cancer reduce oestrogen levels or block oestrogen receptors, it is conceivable that these agents also influence cognitive function. Several small studies have been conducted to address this issue, but many of them are methodologically insufficient. The negative effects of oophorectomy and luteinising hormone-releasing hormone (LHRH) analogues on verbal memory and working memory have been demonstrated the most consistently, albeit only in small studies. Anastrozole and tamoxifen also appear to exert some negative effect on cognition, but well-designed studies are lacking. No data are available on the influence of the aromatase inhibitors exemestane and letrozole on cognitive function. Raloxifene, a drug that has no obvious advantages over tamoxifen and will likely not be developed further for breast cancer treatment, has no negative influence on cognitive functioning. It remains unclear whether the observed effects are transient or permanent, and to what extent age, menopausal status and duration of therapy influence the severity of cognitive effects.     

Invited commentary: Postmenopausal unopposed estrogen and breast cancer risk in the Women's Health Initiative--before and beyond

Three large clinical trials provoked major debate when hormone replacement therapy (HRT) did not reduce coronary heart disease in postmenopausal women as expected from observational epidemiologic studies. Less discussion has ensued about breast cancer or other adverse events. In this issue of the Journal, investigators from the Women's Health Initiative (WHI) compare breast cancer findings from the randomized trial of unopposed estrogen with those from the large WHI observational study. This commentary briefly summarizes historical highlights of menopausal hormone use; risk-versus-benefit evaluations; scientific, clinical, and policy influences immediately before and during the WHI trial; breast cancer incidence trends; and the post-trial response in US clinical practice. Factors complicating interpretation of the results include differences in breast cancer risk profiles between women in the trial and those in the observational study cohort as well as heterogeneity in the definitions of menopause and prior use of HRT as applied by the WHI investigators to the two populations. Because millions of women use HRT, it is important to consider how the WHI and other research investigations might contribute to reducing gaps in understanding the relation between HRT and breast cancer risk.     

Management of Postmenopausal Osteoporosis

Postmenopausal osteoporosis is a very common disease, and approximately half of all women aged >50 years will experience an osteoporotic fracture during the remainder of their lifetime. The predominant cause of postmenopausal osteoporosis is the decline in estrogen levels, which causes an increase in bone turnover, and results in a loss of bone mass throughout the entire skeleton. Fragility fractures, either vertebral or nonvertebral, have a considerable adverse effect on quality of life in women with osteoporosis and place a significant burden on society in terms of healthcare costs.Management of postmenopausal osteoporosis includes alteration of modifiable risk factors (e.g. lifestyle and propensity to fall), ensuring adequate calcium and vitamin D intake, and pharmacological treatment to decrease fracture risk by slowing or preventing bone loss and preserving bone strength. Raloxifene (Evista®), a selective estrogen receptor modulator that partially mimics the effects of estrogen on bone and lipid metabolism and acts as an antiestrogen in the breast and endometrium, is indicated for the prevention and treatment of postmenopausal osteoporosis. Raloxifene increases bone mineral density at vertebral and nonvertebral sites, and decreases the risk of vertebral fracture to a similar extent to the bisphosphonates alendronate and risedronate. However, effects on nonvertebral fracture risk, including the risk of hip fracture, have not been observed.Raloxifene appears to reduce breast cancer risk (in women at average risk) and cardiovascular risk (in women at increased risk) without stimulating the endometrium, and does not cause vaginal bleeding or breast pain. However, the drug causes hot flashes in some women, and increases the risk of venous thromboembolic events by about the same amount as hormone replacement therapy (HRT).In economic models, raloxifene is cost effective compared with no treatment, HRT, calcitonin, or alendronate for the prevention or treatment of postmenopausal osteoporosis.In conclusion, raloxifene is a valuable and cost-effective therapy for preventing the progression of osteoporosis and for reducing vertebral fracture risk in osteoporotic postmenopausal women. The tendency for raloxifene to cause hot flashes, and its apparent lack of effect on hip fracture risk, may preclude its use in women with vasomotor symptoms and in patients at high risk for hip fracture. Results from large ongoing trials are needed to confirm the effects of raloxifene on breast cancer and cardiovascular disease. However, the effects of raloxifene on breast cancer and cardiovascular risk without stimulating the endometrium make the drug an attractive therapy for the prevention and treatment of postmenopausal osteoporosis.     

Medical issues and hormone replacement therapy

The debate surrounding postmenopausal hormone replacement therapy (HRT) has become more contentious in the past decade. The relationship between HRT and venous thrombotic events has been confirmed, although the absolute risk is small. Evidence of a relationship between breast cancer and HRT is stronger. Randomized controlled trials reveal an association with cardiovascular events in women with known heart disease, a possibly diminished overall quality of life due to HRT, and worsening of urinary incontinence. There is also some evidence associating HRT with ovarian cancer. However, longitudinal studies continue to demonstrate over the long term that HRT use is associated with fewer cardiovascular events and a reduced risk of developing dementia. Future studies may show that a lower daily dose of HRT can reduce the risks while still providing benefit.     

Hormone therapy for breast cancer

Breast cancer is a hormone responsive disease, and its proliferation and progression correlate with estrogen. Estrogen binds to estrogen receptor and induces various target genes, thus promoting proliferation of breast cancer cells. Therefore, the strategy of endocrine therapy is the blockade of estrogen action. We can use a luteinizing hormone releasing hormone agonist and aromatase inhibitor as an interruptor of supply, tamoxifen as an inhibitor of estrogen receptor, and medroxyprogesterone acetate with an anti-estrogen action. In this article, we review endocrine therapy for breast cancer patients based on recent clinical trials.